The initiation of the herpes simplex virus lytic replication cycle depends upon the coordinated expression of the viral (IE) immediate early genes. These genes are controlled by a complex multiprotein enhancer assembly that consists of viral and cellular components. Studies of the various components, protein interactions, viral and cellular functions provides both a model for cellular transcriptional regulation as well as insights into the mechanisms utilized by the virus. The focus is the identification and characterization of the critical components of this regulatory pathway. The mammalian coactivator HCF-1 is one of the more complex factors involved in both the assembly of the enhancer complex and the activation of the IE genes. Studies focus upon both functions during the viral lytic cycle as well as in normal cellular processes. The importance of both is underscored by the complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. Recent studies have determined that HCF-1 functions as a component of chromatin modification complexes that are essential for modulating the chromatin status of the viral IE genes upon infection. Additionally, HCF-1 modulate chromatin during HSV-1 DNA replication indicating that the protein plays critical roles throughout the viral lytic replication cycle. In 2013, additional HCF-1 associated histone modulatory complexes and components were identified that are critical elements of the viral IE gene regulatory paradigm. Small molecule inhibitors of these components were identified that block viral IE gene expression upon infection in cell culture and in vivo during primary infection.